ABSTRACT
Alzheimer's disease is an irreversible neurodegenerative disorder affecting approximately 6 million Americans, 90% of which are over the age of 65. The hallmarks of the disease are represented by amyloid plaques and neurofibrillary tangles. While the neuronal characteristics of Alzheimer's disease are well known, current treatments only provide temporary relief of the disease symptoms. Many of the approved therapeutic agents for the management of cognitive impairments associated with the disease are based on neurotransmitter or enzyme modulation. However, development of new treatment strategies is limited due to failures associated with poor drug solubility, low bioavailability, and the inability to overcome obstacles present along the drug delivery route. In addition, treatment technologies must overcome the challenges presented by the blood-brain barrier. This complex and highly regulated barrier surveys the biochemical, physicochemical, and structural features of nearby molecules at the periphery, only permitting passage of select molecules into the brain. To increase drug efficacy to the brain, many nanotechnology-based platforms have been developed. These methods for assisted drug delivery employ sophisticated design strategies and offer serveral advantages over traditional methods. For example, nanoparticles are generally low-cost technologies, which can be used for non-invasive administrations, and formulations are highly tunable to increase drug loading, targeting, and release efficacy. These nanoscale systems can facilitate passage of drugs through the blood-brain barrier, thus improving the bioavailability, pharmacokinetics, and pharmacodynamics of therapeutic agents. Examples of such nanocarriers which are discussed herein include polymeric nanoparticles, dendrimers, and lipid-based nanoparticles.
ABSTRACT
A progressive loss of neuronal structure and function is a signature of many neurodegenerative conditions including chronic traumatic encephalopathy, Parkinson's, Huntington's and Alzheimer's diseases. Mitochondrial dysfunction and oxidative and nitrative stress have been implicated as key pathological mechanisms underlying the neurodegenerative processes. However, current therapeutic approaches targeting oxidative damage are ineffective in preventing the progression of neurodegeneration. Mitochondria-targeted antioxidants were recently shown to alleviate oxidative damage. In this work, we investigated the delivery of biodegradable polyanhydride nanoparticles containing the mitochondria-targeted antioxidant apocynin to neuronal cells and the ability of the nano-formulation to protect cells against oxidative stress. The nano-formulated mitochondria-targeted apocynin provided excellent protection against oxidative stress-induced mitochondrial dysfunction and neuronal damage in a dopaminergic neuronal cell line, mouse primary cortical neurons, and a human mesencephalic cell line. Collectively, our results demonstrate that nano-formulated mitochondria-targeted apocynin may offer improved efficacy of mitochondria-targeted antioxidants to treat neurodegenerative disease.
